Slit2-ROBO signaling in pericytes and myeloid cells controls vascular development and ocular neovascular disease

项目总结 周细胞和髓样细胞与内皮细胞协调形成适当的分支， 功能性血管网络，支持视网膜功能，从而使视力得以恢复。通信中断 眼内皮细胞、周细胞和髓样细胞间的过度病理性血管生成 新生血管疾病，如晚期老年性黄斑变性和糖尿病视网膜病变 导致数百万美国人失明。过度的血管生成目前通过抑制单个血管生成来治疗 只以内皮细胞为靶点的血管内皮生长因子。在这个提议中，我们确定了一种新的Slit2-Robo1&2配体- 通过周细胞中直接受体信号作用促进视网膜新生血管的受体途径 和髓系细胞。通过靶向周细胞和髓系细胞，ROBO在秒内的抑制可能会带来额外的 比单独抑制血管内皮细胞的血管内皮生长因子有好处。我们将定义Slit2-Robo1&2信号的分子基础，并 它在周细胞和髓样细胞中的生物学作用，以揭示控制视网膜发育和 可应用于OND预防的动态平衡。

PROJECT SUMMARY Pericytes and myeloid cells cooperate with endothelium to orchestrate formation of a properly branched, functional vessel network that sustains retinal function and thereby enables vision. Disrupted communication between endothelium, pericytes and myeloid cells leads to excessive and pathological angiogenesis in ocular neovascular diseases (ONDs) such as advanced age-related macular degeneration and diabetic retinopathy that cause vision loss in millions of Americans. Excessive angiogenesis is currently treated by inhibition of a single factor VEGF that targets endothelial cells only. In this proposal we identify a novel SLIT2-ROBO1&2 ligand- receptor pathway that promotes retinal neovascularization through direct receptor signaling effects in pericytes and myeloid cells. By targeting pericytes and myeloid cells, ROBO inhibition in ONDs may confer additional benefit over VEGF inhibition of ECs alone. We will define the molecular basis of SLIT2-ROBO1&2 signaling and its biological role in pericytes and myeloid cells to uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention.